1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) is an important intermediate in the preparation of the active pharmaceutical ingredient known under the International Nonproprietary Name cetirizine. Cetirizine, which is chemically {2-[4-{(4-chlorophenyl)-phenylmethyl}-1-piperazinyl]-ethoxy}-acetic acid, is a non-sedating type antihistamine active ingredient suitable for the treatment of allergy. The effect of cetirizine is based on its selective interaction with histamine H1 receptors inhibiting the histamine release.
Cetirizine is a racemic compound which is per se useful in the therapy. It is known from the state of the art that the administration of the levorotatory enantiomer, (−)-cetirizine is pharmacologically advantageous since during the administration of (−)-cetirizine, less side effects are experienced. (−)-cetirizine is an individual active pharmaceutical ingredient known by the International Nonproprietary Name levocetirizine.
There are several approaches known in the state of the art for the synthesis of optically active compounds.
According to one of these approaches, the racemic end product is prepared and the optically pure enantiomer is obtained in the final step by resolving the racemate.
According to the second approach, the optically active intermediate is prepared in the early phase of the synthesis process and subsequently such a synthetic route is developed, which ensures that the configuration of the desired optical center is retained and prevents the racemization thereof.
For economical reasons, it is desirable to carry out the separation of the optical isomers in an early stage of the synthesis process.
The value of the materials used in the early phase of the synthesis is generally lower than that of the intermediates used in the later stages. This approach usually results in environmental benefits as well, since the side products of the early steps of the synthesis can be more easily disposed of or recycled than those obtained in later stages.
According to a generally accepted procedure in the field of the synthesis of optically active chemicals, those synthesis routes are preferred which allow the use of a previously resolved intermediate known from the art or alternatively, the separation process of the optical isomers provides good yield or the intended optically active intermediate is commercially available.
According to the state of the art, there are three known processes for the preparation of optically active forms of 1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I).
According to the process disclosed in GB Patent No. 2 225 321, racemic 1-(4-chlorophenyl)-phenylmethyl-piperazine is resolved using 2 molar equivalent amount of (R)-tartaric acid and the tartarate salt having unsatisfactory optical purity obtained after three recrystallizations was neutralized. The thus obtained base was crystallized three times from hexane. The process provided (R)-(−)-1-(4-chlorophenyl)-phenylmethyl-piperazine in the yield of 6.3%. This method is not suitable for the use in the pharmaceutical industry since neither the product purity nor the yield are satisfactory.
Similarly to the above-described process, the general method for the separation of the optical isomers comprises preparing diastereomeric salts using an optically active acid, which is the so-called resolving acid. Physical properties of the thus obtained diastereomeric salts (i.e. melting point, solubility etc.) formed from the two optical isomers of the basic compound differ from each other.
Generally, the difference in physical properties of the two optical isomers of the optically active base are significant if the optical center of the optically active base is sterically closely located to the basic nitrogen atom which participates in salt formation.
The separation of the optical isomers of 1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) is a difficult problem because 1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) contains two basic nitrogen atoms. Although one of said nitrogen atoms is sterically closely located to the optical center, this nitrogen atom is sterically hindered therefore the salt formation with this nitrogen atom is hampered. The nitrogen atom distant from the optical center in position 4 undergoes salt formation much more easier.
Furthermore, the resolution of such compounds is complicated by the fact that due to the presence of two basic nitrogen atoms, two molar equivalents of the resolving acid shall be used for salt formation.
Since the optical isomers of racemic 1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) can not be separated with good yield due to the two basic nitrogen atoms, another processes were developed.
In European Patent Application No. 1 236 722, racemic 1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) was acylated in the position 4 and the tertiary butoxycarbonylated derivative of the Formula (V)
was resolved. The acylation in position 4 resulted in that there is one basic nitrogen atom present in the molecule, therefore the amount of the resolving acid can be decreased to one molar equivalents. Salt formation subsequent to acylation takes place at the position sterically close to the optical center, thus the efficacy of the separation could be increased.
The butoxycarbonyl derivative of the Formula (V) was resolved using D-(+)-O,O-dibenzoyl-tartaric acid as resolving acid and the primary product was obtained with an enantiomeric purity of 78%. Subsequently the protecting group was removed by hydrolysis and the base was recrystallized several times.
The disadvantage of the above-mentioned process resides in the fact that the introduction and hydrolytic removal of the protecting group is costly and the yield is only about 30% calculated on the basis of the amount of racemic 1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I).
It is known according to the state of the art that only those protecting groups can be used at the nitrogen atom in position 4 of the piperazine ring of 1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I), which can be removed under mild conditions at low temperature in non-aqeuous solution without the racemization of the optical center.
According to our experience, optically active 1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) is transformed slowly into the corresponding racemic compound in acidic or basic solution even at room temperature. Racemization proceeds rapidly in aqueous alkaline solution, therefore those protecting groups, which are removed by alkaline hydrolysis i.e. acetyl or ethoxycarbonyl group, can not be used without significant racemization.
According to the process disclosed in European Patent No. 617 028, the optical center is prepared in the early phase of the synthesis. (R)-(−)-1-(4-chlorophenyl)-phenylmethylamine of the Formula (VI)
is used as the starting substance. Said compound of the Formula (VI) can be prepared according to the method of Ingold and Wilson using camphorsulphonic acid (J. Chem. Soc. 1933, 1493) or using the process according to Clemo and Gadner in an aqueous solution with (+)-tartaric acid (J. Chem. Soc. 1939, 1958).
The synthesis of the piperazine ring of 1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) is carried out by cyclization reaction. For this reaction, N-substituted derivatives of N,N-bis-(2-chloroethyl)-amine, such as N,N-bis-(2-chloroethyl)-4-methyl-benzenesulphonamide of the Formula (VII)
or N,N-bis-(2-chloroethyl)-benzylamine of the Formula (VIII)
are used, since using N,N-bis-(2-chloroethyl)-amine is accompanied with side reactions and gum formation.
During the synthesis, optically active 1-[(4-chlorophenyl)-phenylmethyl]-4-[p-toluenesulphonyl]-piperazine of the Formula (II)
is obtained by reacting the optically active (4-chlorophenyl)-phenylmethylamine of the Formula (VI) and N,N-bis-(2-chloroethyl)-4-methyl-benzenesulphonamide of the Formula (VII), which is carried out by boiling the reactants in N,N-diisopropyl-ethylamine solvent at the temperature of 127° C. for four hours.
The product is crystallized and the p-toluenesulphonyl group is removed using 30% hydrogen bromide in acetic acid solvent by stirring for 24 hours. Under the harsh reaction conditions, four molar equivalents of 4-hydroxybenzoic acid are used to prevent the racemization. However, by the addition of 4-hydroxybenzoic acid, the process results in a contaminated product. The product is obtained in a yield of approximately 85%. The crude product is further purified by recrystallization.
According to different authors, (Oplatka, C. J. et al., Synthesis 1995, 766) using the above-mentioned process, the optically pure 1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) can be obtained in a yield of 59%.
The disadvantage of the above-mentioned process resides in the fact that the hydrolysis of the toluenesulphonyl group requires harsh reaction conditions. Under such conditions, racemization occur which avoided by using further additives only. Using such additives constitute additional cost and said additives may contaminate the product.
In the field of organic chemistry, the benzyl group is often employed for the protection of nitrogen atoms. The benzyl group can be removed by catalytic hydrogenation using palladium-carbon catalyst at the temperature between 25 and 80° C. or using platinum or Raney-nickel catalyst at higher temperature and at higher hydrogen pressure.
By reacting N,N-(bis-chloroethyl)-benzylamine of the Formula (VIII) with 1-(4-chloromethyl)-methylphenylamine of the Formula (VI) in presence of an acid-binding agent, 1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the Formula (III)
is obtained. However, the benzyl group cannot be removed selectively from 1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the Formula (III) by catalytic hydrogenation using palladium-carbon catalyst, since the N-(4-chlorobenzhydryl) moiety is eliminated faster, than the benzyl group.
According to the disclosure of U.S. Pat. No. 2,709,169, the removal of the N-benzyl group of racemic 1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the Formula (III) can be carried out with the yield of 75% by using the Raney-nickel catalyst. The reaction was carried out at the temperature of 150° C. and the pressure of 100 bar. However, when starting from the optically active benzyl-piperazine derivative, total racemization takes place at this high temperature, therefore the above-mentioned process is not suitable for the preparation of 1-[(4-chlorophenyl)-phenylmethyl]-piperazine of the Formula (I) in the optically active form.
In the case when the compound bis-(2-chloroethyl)-amine protected with the easily removable 2,2,2-trichloroethoxy-group in position 4 corresponding to the Formula (IX)
and 1-(4-chlorophenyl)-methylphenyl-amin of the Formula (VI) are reacted directly, the yield of the desired substituted piperazine derivative of the Formula (IV) is low, because under the conditions of cyclization at the temperature of 100° C. in presence of an acid-binding reagent, the 2,2,2-trichloroethoxy-carbonyl group is removed almost totally.